Benzoate esters of 4-pyrazolidinols



United States Patent 3,542,804 BENZOATE ESTERS OF 4-PYRAZOLIDINOLS Ralph Daniels, Skokie, Ill., assignor to A. H. Robins Company, Incorporated, Richmond, Va., a corporation of Virginia No Drawing. Filed May 9, 1968, Ser. No. 728,065 Int. Cl. C07d 49/02 US. Cl. 260-310 17 Claims ABSTRACT OF THE DISCLOSURE Benzoate esters of 1,2-disubstituted-4-pyrazolidinols are described which are prepared by esterification of the precursor 4-pyrazolidinols, wherein the substituents on the 1 and 2 positions of the 4-pyrazolidinol nucleus are lower alkyl and phenyllower alkyl groups. The esters exhibit good local anesthetic activity, are relatively nontoxic, and have a high therapeutic ratio.

The present invention relates to certain novel esters of 4-pyrazolidinols and is more particularly concerned with benzoate esters of 4-pyrazolidinols, compositions containing the same as active ingredients and methods of making and using them.

The invention is particularly concerned with benzoate esters of 4-pyrazolidinols represented by the following general structural formula:

R Formula I wherein R is selected from the group consisting of lower alkyl and phenyllower alkyl,

R is selected from the group consisting of hydrogen, nitro, lower alkyl, lower alkoxy, halogen having an atomic weight less than 80, amino, lower-alkyl amino and trifluoromethyl,

R is selected from the group consisting of hydrogen, lower al-koxy and halogen having an atomic weight less than 80, and acid addition salts thereof.

The compounds of the invention having the foregoing Formula I represent new chemical compounds which have the capacity to produce physiological action and are adapted more particularly for use as local anesthetics. The local anesthetic properties of the novel benzoate esters of 4-pyrazolidino1s of Formula I were determined by standard pharmacological procedures, including the method of Block, B. P. et al., J. Pharm. Pharmcol. 16, Suppl. 85 T-88T on the earthworm, genus Lumbricus and intradermal administration on the guinea pig, topical administration on the cornea of the rabbit and nerve block in anesthetized rabbits by the methods of Bulbring, E. and Wajda, 1., J. Pharm. and Exptl. Therap. 85, 78-84 (1945) and Chance, M. R. A. and Lobstein, H., J. Pharm. and Exptl. Therap. 82,203 (1944).

In the above referred to procedure of Block et al., the earthworm, genus Lumbricus is placed in a solution of the compound being tested for a period of one minute, dipped in distilled water, dried lightly with absorbent paper and the tail dipped in 0.0125 N hydrochloric acid. The local anesthetic action is shown by the absence of a sharp contracting response in the worm and the duration of action is measured from the application of acid until a response is noted. In the following table compounds of Patented Nov. 24, 1970 the invention are compared with the known local anesthetic Lidocaine (diethylaminoacet-2,6-xylide.)

TAB LE I Concentra- Average tion of test time for solution, response pH of Compound percent (mins) solutlon 2. 00 2. 0 6. 69 Ldocane 1. 00 4. 0 6. 68 0. 50 7. 0 6. 68 1,2-diethyl-4-pyrazolidinol 3- 5. 00 l. 0 3. 88 trifluoromethylbenzoate O. 08 2. 0 6. 01 0. 04 6. 0 6. 35 0. 02 11. 0 6. 49 1,2-diethy1-4-pyrazolidinol 4- g imethylbenzoate 31 0 32 0. 16 2. 0 5. 58 0. 08 5. 5 6. 10 1,2-dimethyl-4-pyrazolidinol benzoate 5. 00 4. 0 3. 57

Moreover, the novel benzoate esters of the 4-pyrazolidinols of the present invention have a low order of toxicity resulting in a favorable therapeutic ratio. The acute LD s in mice (female albino mice; Dublin Laboratory Animals, Inc. ICR Strain) weighing 20-24 grams was determined by injecting solutions of the compounds into the lateral tail vein at a constant volume of .05 ml./ 10 gms. of weight and at a constant rate of .05 ml./1O seconds. A comparison of the LD s of some of the cornpounds of the invention with Lidocaine is shown in Table 11.

TABLE II Compound: 'LD (Intravenous) mg./kg. Lidocaine 45.7

1,2 diethyl 4 pyrazolidinol p methoxybenzoate 204.5

1,2 diethyl 4 pyrazolidinol p-chlorobenzoate 182.4

l,2-diethyl-4-pyrazolidinol p trifluoromethylbenzoate 245.6 1,2-diethyl-4-pyrazolidinol p fluorobenzoate 377.0

When the benzoate esters were given intraperitoneally, no animals died at a maximum dose level given of 1500 mg./l g.

The local anesthetic action determined by intradermal administration on guinea pigs was carried out on female albino guinea pigs (Lightner Enterprises) weighing 270 to 335 grams. Intradermal injections were made using concentrations of 1, 3, and 10 m-g./kg. The injected volume of all test solutions was 0.2 ml. A local anesthetic effect was produced with all compounds while normal saline was totally inactive. The results are given in Table II-A.

T AB LE II-A Percent reduction in responses, minutes after Concentreatment tration, Compound rug/ml. 0 5 15 30 60 1 35 15 4 0 Lidocaine 3 62 19 6 0 10 58 70 15 0 1,2-diethyl4-pyrazolidinol 4- 1 17 0 0 0 methoxybenzoate 3 33 8 0 0 10 50 0 8 0 1,2-diethyl-4-pyrazolidinol 4- l 17 8 0 0 chlorobenzoate 3 33 0 0 0 10 83 25 0 0 1,2-diethyl-4-pyrazolidinol 4- 1 0 8 O 0 tlifluoromethyl benzoate.-. 3 33 8 8 O 10 42 8 0 1,Z-diethylA-pyrazolidinol 4- 1 50 8 0 0 fluorobenzoate 3 75 25 17 0 l0 67 58 17 0 The present invention further contemplates the use of the novel compounds in mammals when local anesthesia is desired. In topical anesthesia as in relieving pruritus preparations containing l2% of the esters as their salts are prepared and may be used as such in sprays,, lotions and ointments. Preparations useful for infiltration, nerve block, spinal, peridural and caudal anesthesia are usually prepared as sterile aqueous solutions of the salts of the esters, the solutions containing from 0.5% to of the active ingredient.

It is, accordingly, an object of the present invention to provide novel benzoate esters of 4-pyrazolidinols. Another object is to provide novel compounds which, when administered to mammals, provide local anesthetic action with minimum side effects. A still further object of the present invention is to provide methods for producing the novel benzoate esters of 4-pyrazolidinols and methods for the utilization thereof. Additional objects will become apparent hereinafter and still others will be apparent'to one skilled in the art.

In the definition of symbols in the foregoing Formula I and where they appear elsewhere throughout this specification the terms have the following significance:

The term lower alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive, preferably no more than six carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

The term lower alkoxy has the formula Olower alkyl.

The term phenyllower-alkyl refers to groups such as benzyl, phenethyl, o-methylbenzyl, phenpropyl and the like.

This invention also includes acid addition salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known in the art. When the compounds are to be used as intermediates for preparing other compounds or for any other non-pharmaceutical use, the toxicity or nontoxicity of the salt is immaterial; when the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of nontoxic acid-addition salts. Both toxic and nontoxic salts are therefore within the purview of the invention. The acids which can be used to prepare the preferred nontoxic acid-addition salts are those which produce, when combined with the free bases, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side effects ascribable to the anions.

The base is reacted with the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and cooling, or the base is reacted with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or isopropyl ether, with the desired salt separating directly. Exemplary of such organic salts are those formed with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamic, p-aminobenzoic, glutamic, stearic acid and the like. Exemplary of such inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The novel benzoate esters of 4-pyrazolidinols of this invention as represented by Formula I above are prepared by esterification of l,2-disubstituted-4-pyrazolidinols of Formula II I OH R wherein R is as defined above.

Symmetrical disubstituted hydrazines prepared by methods described in the literature are mixed with epichlorohydrin in a molar ratio of about 1:1 to about 2:1 and preferably 1.521 in a dry inert organic solvent, illustratively ether in a dry flask.

Formula II The flask is stoppered and allowed to stand at a temperature from about 0 C. to about 24 C. for a period of from about four days to about twenty-four days. After the reaction period the precipitated disubstituted hydrazine hydrochloride is removed by filtration, or the reaction mixture is treated with an excess of an aqueous alkali metal carbonate solution, the organic solvent is separated from aqueous material, dried briefly over a drying agent and evaporated and the residual oil distilled in vacuo to give the l,2-disubstituted-4-pyrazolidino1s of Formula II.

Generally speaking, the method of preparing the compounds of Formula I is as follows: A 1,2-disubstituted-4- pyrazolidinol is reacted with an appropriately substituted benzoic acid in an inert organic solvent, illustratively benzene, containing a catalytic amount of a mineral acid or an aryl sulfonic acid and the water formed during the esterification process is removed azeotropically. After completion of the reaction as determined by the amount of water collected, the reaction mixture is washed with water, dried over an inert drying agent, the solvent removed and the residual crude ester purified by conventional procedures including distillation, crystallization, chromatography and the like. Alternatively, the substituted benzoic acid is converted first to the acid halide by reaction with a thionyl halide and the substituted benzoyl halide thus formed is reacted, after suitable purification, with the 1,2-disubstituted-4-pyrazolidinol. The reaction mixture from the latter procedure is quenched in water, an excess of a metal carbonate added, and the base insoluble ester extracted with an organic solvent and the ester isolated and purified as described hereinabove.

In the preferred method of preparing the novel esters of Formula I, a solution of the 4-pyrazolidinol in anhydrous pyridine is treated with a slight excess of an appropriately substituted benzoyl chloride. The initial reaction which is usually exothermic is allowed to cool to room temperature and the reaction is completed by heating the reaction mixture on a steam bath for a period of from about thirty minutes to one hour or by allowing the reaction mixture to stand at room temperature for a period of from about two days to about four days. The reaction mixture is poured into water, an excess amount of a metal carbonate is added as, for example, potassium carbonate, and the base insoluble ester extracted using an organic solvent. The organic solvent is removed after drying, using an inert drying agent, illustratively magnesium sulfate, and the residual ester purified by distillation or by conversion to an acid addition salt.

The following examples are presented to illustrate the present invention and they should not be construed as limiting it in spirit or in scope:

EXAMPLE 1 1,2-dimethyl-4-pyrazolidinol Into a dried 200 ml. Erlenmeyer flask were placed 100 ml. of anhydrous ether, 15.8 g. (0.263 mole) of 1,2-dimethylhydrazine, and 16.2 g. (0.175 mole) of epichlorohydrin. The flask was placed in the refrigerator at a temperature of 4 C. for a period of 10 days. The ether solution was filtered free of precipitated salt and the ether filtrate was concentrated in vacuo on the water bath. The oily residue was distilled at 56 C. (0.1 mm.) to give 7.4 gms. (36.4%) of a colorless mobile oil. A picrate melted at l-l76 C.

Analysis.Calculated (percent) for C H N O: C, 51.70; H, 10.41; N, 24.12. Found (percent): C, 51.92; H, 10.53; N, 23.84.

EXAMPLE 2 1,2-diethyl-4-pyrazolidinol Into a dried 250 ml. Erlenmeyer flask were placed ml. of anhydrous ether and 16.1 g. (0.183 mole) of 1,2- diethylhydrazine and 11.3 g. (0.122 mole) of epichlorohydrin. The flask was stoppered and allowed to stand at room temperature for about one week. The ether solution was treated with an excess of aqueous potassium carbonate solution and dried over magnesium sulfate. The dried ether solution was flash evaporated and the oily residue was distilled at reduced pressure. A total of 9.3 g. (53.0%) of product collectedat 53 C./ 0.03 mm.

Analysis-Calculated (percent) for C H N O: C, 58.43; H, 11.18, N, 19.43. Found (percent): C, 58.18; H, 11.61; N, 19.18. i

' EXAMPLE 3 1,Z-dibenzyl-4-pyrazolidinol Into a 500 ml. Erlenmeyer flask were placed 8.45 g. (0.091 mole) of epichlorohydrin, 200 ml. of anhydrous ether, and 38.7 g. (0.183 mole) of 1,2-dibenzy1hydrazine. The glass stoppered Erlenmeyer flask was stored at room temperature for a period of 18 days. The precipitated white solid which separated was filtered and the ether distilled from the filtrate under reduced pressure using a water bath. The oily residue solidified to a waxy mass which melted at 80-84 C. after crystallization from ligroin. The solid obtained after crystallization from benzene weighed 10.0 gms. (40.8%) and melted at 91.5- 920 C.

Analysis.-Calculated (percent) for C H N O: ,C,

76.08; H, 7.51; N, 10.44. Found (percent): C, 76.42; H, 7.67; N, 9.99.

EXAMPLE 4 1,2-di-n-propyl-4-pyrazolidinol In the same manner as given in Examples 1-3, 1,2-din-propyl-4-pyrazolidinol was prepared from 1,2-di-n-propylhydrazine and epichlorohydrin. The free base wasa colorless oil that distilled at 60-62" C./ 0.05 mm.

Analysis-Calculated (percent) for C H N O: C,

62.75; H, 11.70; N, 16.26. Found (percent): C, 63.22; H,

7 EXAMPLE 1,2-di-isopropyl-4-pyrazolidinol In the same manner as given in Examples 1-3, 1,2-diisopropyl-4-pyrazolidinol was prepared from 1,2-di-isopropylhydrazine and epichlorohydrin. The free base distilled at 54 C./0.09 mm.

Analysis.Calculated (percent) for C H N O: C, 62.75; H, 11.70; N, 16.26. Found (percent): C, 63.26; H,

1,2-diphenethy1-4-pyrazolidinol In the same manner as given in Example 3, 1,2-diphenethyl-4-pyrazolidinol is prepared from 1,2-diphenethylhydrazine and epichlorohydrin.

EXAMPLE 8 1,Z-diphenpropyl-4-pyrazolidinol In the same manner as given in Example 3, l,2-diphenpropyl-4-pyrazolidinol is prepared from 1,2-diphenpropylhydrazine and epichlorohydrin.

, EXAMPLE 9 1,2-dimethyl-4-pyrazolidinyl benzoate hydrochloride Three g. (0.01 mole) of 1,Z-dimethyl-4-pyrazolidinol was dissolved in about 30 ml. of anhydrous pyridine. To

this solution was added dropwise, 1.5 g. (0.01 mole) of benzoyl chloride. After the initial exothermic reaction subsided the solution was heated on a steam bath for about 30 minutes and then poured into a beaker containing 30 ml. of water. The solution was neutralized with 20 ml. of a 5% sodium carbonate solution, extracted with three 50 ml. portions of ethyl acetate, and the combined organic extracts were dried and evaporated in vacuo. The residual brown oil was dissolved in absolute ether and dry hydrogen chloride gas was passed through the ether solution to yield an oil that solidified to a tan solid. The ether was evaporated to give a crude product melting at 153-157" C. after drying. The product was crystallized from a 1:1 mixture of acetone and heptane to give a white amorphous solid that melted at 158-159.5 C. and weighed 2.2 g. (75% yield).

Analysis.-Calcd for C12H17N2O2C1 (percent): C, 56.14; H, 6.68; N, 10.91; Cl, 13.81. Found (percent): C, 56.40; H, 6.79; N, 10.98; Cl, 13.90.

EXAMPLE 10 1,2-dimethyl-4-pyrazolidinyl 4-nitrobenzoate hydrochloride To a flask containing 5 g. (0.05 mole) of 1,2-dimethyl- 4-pyrazolidinol was added 25 ml. of anhydrous pyridine and to this solution was added 3.6 g. (0.043 mole) of 4- nitrobenzoyl chloride. The solution was heated on a steam bath to effect solution and then heated carefully on an open flame for about five minutes. The brown solution was poured into a 5% solution of sodium bicarbonate. The solution was extracted with ether and the ether evaporated to give a yellow solid. The yellow solid was dissolved in absolute ethanol and dry hydrogen chloride gas was passed into the solution. The solution was evaporated in vacuo and the residual oil was dissolved in n-propanol and cooled. The n-propanol was evaporated in vacuo to give a light yellow solid. Recrystallization of the solid from a 1:1 mixture of acetone-isopropanol gave 2 g. (15%) of product, M.P. 215-216 C.

Analysis.Calcd for C H N O Cl (percent): C, 47, 77; H, 5.34; N, 13.94; Cl, 11.75. Found (percent): C, 47.93; H, 5.51; N, 13.89; Cl, 11.90.

Using the procedure described above, the following compounds are prepared from the stated ingredients:

1,2 diethyl 4 pyrazolidinyl 2-methoxy-4-nitrobenzoate is prepared from 1,2-diethyl-4-pyrazolidinol and 2- methoxy-4-nitrobenzoyl chloride,

1,2 diethyl 4 pyrazolidinyl 2-propoxy-4-nitrobenzoate is prepared from 1,2-diethyl-4-pyrazolidinol and 2- propoxy-4-nitrobenzoyl chloride.

' EXAMPLE 11 1,2-diethyl-4-pyrazolidinyl benzoate hydrochloride Into a 50 ml. Erlemmeyer flask were placed 12 g. (0.83 mole) of 1,2-diethyl-4-pyrazolidinol and 15 ml. of anhydrous pyridine. Benzoyl chloride (14.0 g.; 0.1 mole) was added slowly to the pyridine solution. The solution became dark and quite warm and was allowed to stand at room temperature over the week end. The mixture was poured into an aqueous solution of 5% potassium carbonate and solid potassium carbonate was added until the evolution of carbon dioxide ceased. The solution was extracted with ethyl ether and the extract was dried with anhydrous magnesium sulfate. The ether and pyridine was removed in vacuo and the red, oily residue was dissolved in anhydrous ethyl and dry hydrogen chloride was passed through the solution. An oil separated and slowly solidified after standing for about one week. The brown solid was recrystallized repeatedly from acetone and yielded 15.1 g. (64%) of product which melted at 134-136 C.

Analysis.-Calcd for C H N O Cl (percent): C, 59.04; H, 7.43; N, 9.84; CI, 12.45. Found (percent): C, 58.94; H, 7.36; N, 9.66; CI, 12.46.

Using the procedure described above, the following 1,2-diethyl-4-pyrazolidinyl 2-propoxy-4-aminobenzoate is compounds are prepared from the stated ingredients: prepared by catalytic hydrogenation of 1,2-diethyl-4- 1,2 diethyl 4 pyrazolidinyl-2-ethoxy-4-fluorobenzoate pyrazolidinyl 2-propoxy-4-nitrobenzoate.

is prepared from 1,2-diethyl-4-pyrazolidinol and 2- ethoxy-4-fluorobenzoyl chloride, 5 EXAMPLE 24 1,2 dlefthyl 4 PYFaZOhdmYI-Z-PYOPOxv-4-flqorobenl,2-diethyl-4-pyrazolidinyl 4-(n-butylamino)-benzoate zoate is prepared from 1,2-d1ethyl-4-pyrazolid1nol and 2-propoxy-4-fluorobenzoyl chloride, Into a three-necked 500 ml. round bottom flask were 1,2 diethyl 4 pyrazolidinyl 2-fiuorobenzoate is preplaced 30 g. (0.11 mole) of 1',2-diethyl-4-pyrazolidinyl ppared from l,2-diethyl-4-pyrazolidinol and 2-fluoroaminobenzoate, 130 ml. of benzene and 31 ml. (0.50

benzoyl chloride, mole) of glacial acetic acid. Powdered zinc dust (32 g.;

1,2 diethyl 4 pyrazolidinyl-B-fluor0benzoate is pre- 0.50 111016) was added and the contents 0f the flask was pared from 1,2-diethyl-4-pyrazolidinol and 3-fluorostirred mechanically under reflux while n-butraldehyde benzoyl chloride, (13.3 ml., 0.15 mole) was added over a period of two EXAMPLES 12 22 15 hours. The mixture was st1rred for about two hours longer and then filtered while hot through a fluted filter paper. Examples 1222 were prepared by methods analagous The filtrate was treated with potassium hydroxide to those described for Examples 9-11. The physical consolution until the aqueous layer was basic to litmus. The stants of Examples 12-22 are shown in Table III. organic layer was separated, dried with anhydrous mag- TABLE III-EXAMPLES 12-22 [Esters of 1,2-disubstltuted-4-pyrazolldinols] Analysis 0, percent H, percent N, percent 01, percent Mis., percent Example R R l R 2 M.P., C. Caled. Found Calcd. Found Calcd. Found Calcd. Found Calcd. Found H 134-136 55. 72 63 6. 6. 54 9. 28 9. 21 11. 71 11. 71 F, 6.27 F, 6.46.

H 131-132. 5 46. 24 46 16 4. 07 4. 03 12. 84 12. 92 F, 10.45 F, 10.62.

1 Analysis of hydrochloride salt.

2 Analysis of plcrate.

8 Analysis of hydrochloride salt-semi-cyclohexane solvatc. 4 Analysis of free base.

5 Melting point of picrate.

* Boiling point 126128/.02 mm.

EXAMPLE 23 nesium sulfate and flash evaporated. The light yellow oil that remained solidified on storing over night to a light tan solid. The solid was recrystallized from cyclohexane to Into a ml. Erlenmeyer flask were placed 28.8 g. 45 give 20 g. (55%) of product; M.P. 6l-63 C. A picrate 1,2-diethyl-4-pyrazolidinyl 4-aminobenzoate mole) of y 'Py and about 30 was prepared and was recrystallized from absolute alcoml. of anhydrous pyridine and 38 g. (0.2 mole) of 4- 1 1; M,P 132 133 C, nitrobenzoyl chloride was added slowly. The reaction A l i f t c l l t d for C H N O (percent):

mixture became warm and turned dark red. After cooling C, 6758; H, 9,15; N, 13,15, Fo nd ent); C, 67.67; in an ice-water bath, the material was heated on the steam 50 H, 913; N, 13,07,

bath for about 15 minutes, at which time it solidified. Analysis of picrate: Calculated for C H N O (per- The flask was allowed to cool to room temperature. The ent): C, 52.55; H, 5.88; N, 15.32. Found (percent): C, solid was dissolved in about 100 ml. of water and the solu- 52 63; H, 5 73; N, 1533,

tion saturated with potassium carbonate. The dark red V i difi ti may b d i h present i Oil that Separated was eXtfaCted With ether, dried, and 55 vention without departing from the spirit and scope thereflash p The residual Fed Oil Was transferred to of, and it is to be understood that the invention is limited at pressure bottle containing a suspension of 0.5 g. Pt0 only by h scope f the appended 1 in ml. methanol. The bottle was shaken on the Parr What is claimed apparatus in an atmosphere of hydrogen A total of 43 1. A compound selected from the group of benzoate Pounds of y) of hydrogen Was taken P in 60 esters of 1,2-disubstituted-4-pyrazolidinol having the forone hour. No appreciable amount of hydrogen was taken l up on additional shaking. The mixture was filtered and R N O R concentrated to give a grey-green solid. The yield of the ll crude solid was 47.3 g. The compound was recrystallized R N from about one liter of cyclohexane to give 37 g. (69%) 65 R2 of solid melting at 82-85 C. wherein;

Analysis.Calcd for C H N O (percent): C, R is selected from the group consisting of lower alkyl 63.85; H, 8.04; N, 15.96. Found (percent): C, 63.92; H, and phenyllower-alkyl,

8.15; N, 15.88. R is selected from the group consisting of hydrogen, Using the catalytic reduction procedure described 70 nitro, lower alkyl, lower alkoxy, ge having 4 above, the following compounds are prepared from the atomic weight less than 80, amino, lower-alkyl amino stated ingredients: and trifiuoromethyl,

1,Z-diethyl-4-pyrazolidinyl 2-methoxy-4-aminobenzoate is R iS elected from the group consisting of hydrogen, prepared by catalytic hydrogenation of 1,2-diethyl-4- lower alkoxy and halogen having an atomic weight pyrazolidinyl 2-methoxy-4-nitrobenzoate, less than 80 and acid additive salts thereof.

2. A compound according to claim 1 which is 1,2-dimethyl-4-pyrazolidinyl benzoate.

3. A compound according to claim 1 which is 1,2- dimethyl-4-pyrazolidinyl-4-nitrobenzoatc.

4. A compound according to claim dicthyl-4-pyrazolidinyl benzoate.

5. A compound according to claim diethyl-4-pyrazolidinyl 4-fiuorobenzoate.

6. A compound according to claim 1 which dicthy1-4-pyrazolidinyl B-trifluoromethylbenzoate.

7. A compound according to claim 1 which diethyl-4-pyrazolidinyl 4-methylbenzoate.

8. A compound according to claim 1 which diethyl-4-pyrazolidinyl 4-amyloxybenzoate.

9. A compound according to claim 1 which diethyl-4-pyrazolidinyl 2,4-dichlorobenzoate.

10. A compound according to claim 1 which is diethyl-4-pyrazolidinyl Z-methoxybenzoate.

11. A compound according to claim 1 which is dibenzy1-4-pyrazolidinyl benzoate.

12. A compound according to claim 1 Which is dibenzy1-4-pyrazolidiny1 4-fluorobenzoate.

1 which is 1,2-

1 which is 1,2-

13. A compound according to claim 1 which is 1,2- diethyl-4-pyrazolidiny1 4-methoxybenzoate.

14. A compound according to claim 1 which is 1,2 diethyl-4-pyrazolidinyl 4-trifluoromethylbenzoate.

15. A compound according to claim 1 which is 1,2- diethy1-4-pyrazolidinyl 4-chlorobenzoate.

16. A compound according to claim 1 which is 1,2 diethyl-4-pyrazolidinyl 4-aminobenzoate.

17. A compound according to claim 1 which is 1,2 diethyl-4-pyrazolidinyl 4-(n-butylamino)-benzoatc.

References Cited Morrison et a1., Organic Chemistry, 2nd Edition, Allyn and Bacon, Inc., Boston, Mass., 1966, p. 671.

HENRY R. JILES, Primary Examiner G. THOMAS TODD, Assistant Examiner U.S. CI. X.R. 424273 

